Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity
, Lucia Dello Iacono 1, Cecilia Pozzi 1, Chiara Borsari 2, Stefania Ferrari 2, Matteo Santucci 2, Nuno Santarem 3, Anabela Cordeiro-da-Silva 3, Carolina B. Moraes 4, Laura M. Alcantara 4, Vanessa Fontana 4, Lucio H. Freitas-Junior 4,5, Sheraz Gul 6, Maria Kuzikov 6, Birte Behrens 6, Ina Pöhner 7, Rebecca C. Wade 7,8,9, Maria Paola Costi 2,*
and Stefano Mangani 1,10,*
Abstract
Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1–3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1–TbPTR1 and Leishmania major–LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants. View Full-Text
Graphical abstract
Share & Cite This Article
Di Pisa, F.; Landi, G.; Dello Iacono, L.; Pozzi, C.; Borsari, C.; Ferrari, S.; Santucci, M.; Santarem, N.; Cordeiro-da-Silva, A.; Moraes, C.B.; Alcantara, L.M.; Fontana, V.; Freitas-Junior, L.H.; Gul, S.; Kuzikov, M.; Behrens, B.; Pöhner, I.; Wade, R.C.; Costi, M.P.; Mangani, S. Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity. Molecules 2017, 22, 426.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.